Ultrasound‐triggered effects of the microbubbles coupled to GDNF‐ and Nurr1‐loaded PEGylated liposomes in a rat model of Parkinson's disease

Abstract

The purpose of this study was to investigate ultrasound-triggered effects of the glial cell line-derived neurotrophic factor (GDNF) + nuclear receptor-related factor 1 (Nurr1)-polyethylene glycol (PEG)ylated liposomes-coupled microbubbles (PLs-GDNF + Nurr1-MBs) on behavioral impairment and neuron loss in a rat model of Parkinson's disease (PD). The unloaded PEGylated liposomes-coupled microbubbles (PLs-MBs) were characterized for zeta potential, particle size, and concentration. 6-hydroxydopamine (6-OHDA) was used to establish the PD rat model. Rotational, climbing pole, and suspension tests were used to detect behavioral impairment. The immunohistochemical staining of tyrosine hydroxylase (TH) and dopamine transporter (DAT) was used to assess the neuron loss. Western blot and quantitative real-time PCR (qRT-PCR) analysis were used to measure the expression levels of GDNF and Nurr1. The particle size of PLs-MBs was gradually increased, while the concentration and absolute zeta potential were gradually decreased as the time prolongs. 6-OHDA increased amphetamine-induced rotations and loss of dopaminergic neurons as compared to sham group. Interestingly, PLs-GDNF-MBs or PLs-Nurr1-MBs decreased rotations and increased the TH and DAT immunoreactivity. Combined of both genes resulted in a robust reduction in the rotations and a greater increase of the dopaminergic neurons. The delivery of PLs-GDNF + Nurr1-MBs into the brains using magnetic resonance imaging (MRI)-guided focused ultrasound may be more efficacious for the treatment of PD than the single treatment.

Blood–brain barrier opening with focused ultrasound in experimental models of Parkinson's disease

“…The combination of GDNF‐loaded microbubbles and FUS resulted in restored behavioral motor deficits and ameliorated neuronal death in the SNc and dopamine loss in the striatum of 6‐OHDA‐trated rats. In a similar approach, the delivery of GDNF alone or in combination with nuclear receptor‐related factor1 with polyethylene glycolylated liposomes–coupled microbubbles using FUS alleviated the behavioral deficits and neuron loss in the 6‐OHDA rats . The multistep process involved in gene transfection requires successful delivery, translation, and release followed by receptor ligation.…”

“…In a similar approach, the delivery of GDNF alone or in combination with nuclear receptor-related factor1 with polyethylene glycolylated liposomes-coupled microbubbles using FUS alleviated the behavioral deficits and neuron loss in the 6-OHDA rats. 56,57 The multistep process involved in gene transfection requires successful delivery, translation, and release followed by receptor ligation. It is therefore subjected to limited efficacy, shifting the scientific interest toward direct protein delivery.…”

Exploiting Focused Ultrasound to Aid Intranasal Drug Delivery for Brain Therapy

“…On the side of NDs, the FUS mediated opening of the BBB has been used to explore innovative therapies for AD ( Raymond et al, 2008 ; Jordão et al, 2010 ; Leinenga and Gotz, 2015 , Nisbet et al, 2017 ; Janowicz et al, 2019 ), PD ( Kinoshita et al, 2006 ; Lin et al, 2016 ; Chen et al, 2016 ; Mead et al, 2017 ; Yue et al, 2018a , Yue et al, 2018b ; Karakatsani et al, 2019 ), Huntington ( Burgess et al, 2012 ). In august 2021 a survey of the Clinical Trials Database ( https://www.clinicaltrials.gov ) resulted in a total of 19 studies ( Table 1 ), of which 3 with a completed status ( Lipsman et al, 2018 ; Abrahao et al, 2019 ; Mainprize et al, 2019 ), 7 active and nine recruiting.…”

Ultrasound-Responsive Materials for Drug/Gene Delivery

“…Ultrasound-responsive material-based drug/gene delivery has been explored widely in treating cancer (Khokhlova et al, 2015;Qin et al, 2016;Fan et al, 2017;Yue et al, 2018;Jing et al, 2019), cardiovascular diseases (Hua et al, 2014;Dixon et al, 2015;Castle and Feinstein, 2016), orthopedic diseases (Le et al, 2016;Pullan et al, 2017;Kuo et al, 2019), ocular diseases (Aptel and Lafon, 2012;Wan et al, 2015a;Wan et al, 2015b;Lafond et al, 2017) and brain diseases (Timbie et al, 2015;Song et al, 2018a), and also applied in vaccine immunization (Tachibana et al, 1997;Escoffre et al, 2016). However, application of ultrasound-responsive materials in drug/gene delivery faces certain challenges.…”